PROJECT SUMMARY The host immune response is critical for the clearance of head and neck cancer during chemoradiotherapy (CRT). Recent findings suggest impairment of this crucial response during standard CRT. Therefore, to block impairment of the host immune response we have developed a novel chemoimmunotherapy (CIRT) regimen incorporating the PD-1 inhibitor, pembrolizumab. We hypothesize that this novel CIRT regimen will overcome the exhausted immune phenotype evident during standard CRT, thereby facilitating the immune response and enhancing tumor clearance. We will test this hypothesis by comparing the peripheral blood immunocyte response during standard CRT and CIRT. Patient immune phenotype and functional response during treatment will be assessed by flow cytometry, immunocyte immune checkpoint and cytokine expression. In patients with human papilloma virus (HPV) related cancers, retention of the HPV specific immune response will be compared. In addition, we will investigate tumor and tumor microenvironment factors that may impact the host immune response. Pre-treatment tumor infiltrating lymphocyte (TIL) populations, immune checkpoint expression, and immune-related gene signatures will be correlated with clinical outcome and peripheral blood immune response in patients treated with standard CRT and CIRT. In patients who do not respond to treatment, salvage surgical specimens will be evaluated to identify factors that contributed to treatment resistance. With the increasing availability of numerous immunotherapy options, this project will provide important insights into immune biomarkers and identify targets for future therapeutic interventions.